Metastasis to the Cervix Uteri 15 Years After Treatment of Lobular Carcinoma of the Breast

CURRENT CLINICAL PRACTICE

Metastasis to the Cervix Uteri 15 Years After Treatment of Lobular Carcinoma of the Breast Adrienne G. Waks,1 James Lennon,1 Budhi S. Yadav,2 Helena Hwang, Marcela dSchapirael Carmen, Nicole B. Johnson, Kerry Reynolds, Lidia Schapira, Paul B. Gilman, and Beth Overmoyer

At times we encounter clinical problems for which there are no directly applicable evidence-based solutions, but we are compelled by circumstances to act. When doing so we rely on related evidence, general principles of best medical practice, and our experience. Each “Current Clinical Practice” feature article in Seminars in Oncology describes such a challenging presentation and offers treatment approaches from selected specialists. We invite readers’ comments and questions, which, with your approval, will be published in subsequent issues of the Journal. It is hoped that sharing our views and experiences will better inform our management decisions when we next encounter similar challenging patients. Please send your comments on the articles, your challenging cases, and your treatment successes to me at dr.gjmor [email protected]. I look forward to a lively discussion. Gloria J. Morris, MD, PhD Current Clinical Practice Feature Editor

I

nvasive lobular carcinoma (ILC) represents the second

Conflicts of interest: none Address correspondence to Gloria J. Morris, MD, PhD, Editor, Current Clinical Practice, Hematology/Oncology Associates of Central New York, PC, East Syracuse, NY 13057. E-mail: [email protected] 1 Drs Waks and Lennon contributed equally to the writing of this manuscript. 2 Case was submitted by Dr Yadav.

0093-7754/ - see front matter & 2015 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1053/j.seminoncol.2015.07.002

most common histologic subtype of invasive breast cancer, accounting for approximately 10% of all invasive breast cancers,1–6 whereas invasive ductal carcinoma (IDC), by contrast, constitutes 70%–80% of invasive breast cancers.6 There are both histologic and biological differences between ILC and IDC. For example, the typical histopathology of ILC consists of small monomorphic neoplastic cells with bland round nuclei invading normal tissue stroma in strands or chains in a single file pattern.7 ILCs are typically well differentiated, more commonly positive for surface expression of the estrogen receptor (ER) and progesterone receptor (PR), and negative for HER2/ neu amplification.8–10 Occasionally, ILC cases can show large and pleomorphic nuclei, and are thus classified as pleomorphic ILC; rarely, they can be Her2-positive.11 ILC and IDC have distinct metastatic patterns. Locally, lobular carcinomas are more commonly multicentric and bilateral when compared to other invasive tumors of the breast. They have a tendency not to form distinct masses, making it more difficult to detect on routine screening modalities such as a mammogram. Due to these characteristics, breast-conserving therapies can be problematic.12 Distantly, ILC tends to diffusely infiltrate organs and surfaces in the peritoneum

Seminars in Oncology, Vol 42, No 4, August 2015, pp e81-e94

and retroperitoneum, including the uterine myometrium, endometrium, and cervix, as well as ovaries, ureters, and stomach (in which it produces a characteristic “linitis plastica”-type appearance).2,6 In one series, six of 14 ILC patients were found to have uterine metastases at autopsy. Carcinomatous meningitis is also preferentially associated with lobular carcinoma.6 Breast cancer is furthermore the most common nongenital malignancy to metastasize to the uterus,13 presumably owing to the behavior of the lobular subtype. The reason for these differences in the metastatic patterns between ILC and IDC has never been fully understood but it is thought that the loss of a functional E-cadherin transmembrane adhesion molecules plays an important role in the unusual metastatic pattern of ILC,14 and ascribes a poorly cohesive nature.15 A case is presented here as follows.

CASE SUMMARY A 53-year-old menopausal Indian female presented to an outpatient clinic with a 2-month history of postcoital bleeding. She was examined by a gynecologist who detected a growth on the uterine cervix upon vaginal examination. A biopsy was taken, which was initially reported as “poorly e81

e82

A.G. Waks et al

Figure 1. A panel of microphotographs. (a & b) Small tumor cells present in nests and in prominent “Indian file” pattern (hematoxylin and eosin [H&E] 20x); (c) Indian file pattern of tumor cells present in desmoplastic stroma (H&E 40x); (d) tumor cells infiltrating the endocervical stroma with intact benign endocervical glands (H&E 40x).

differentiated squamous cell carcinoma” and she was staged clinically as having International Federation of Gynecology and Obstetrics (FIGO) stage IIB cervical carcinoma. She had a history of premenopausal breast cancer diagnosed at age 38, when she had presented at an outside hospital with a mass in her right breast, from which fine-needle aspiration cytology revealed ILC. She subsequently underwent breast-conservation surgery with axillary lymph node dissection, which yielded final stage T2N1M0. Postoperatively, she received chemotherapy (methotrexate þ cyclophosphamide þ 5-fluorouracil [5-FU]) and radiation therapy (50 Gy in 25 fractions over 5 weeks). The tumor was reportedly positive for expression of ER and PR, and she was thus given tamoxifen for 5 years. She was clinically disease-free, and underwent regular follow-up until the present. At this time, 15 years later, she was subsequently referred to a

tertiary care facility for the treatment of presumed cervical cancer. Biopsy slides from the outside hospital were re-reviewed onsite and showed small-sized tumor cells present in solid sheets and nests and in a prominent single-file pattern (Figure 1) in desmoplastic stroma. The tumor cells were seen infiltrating the endocervical stroma with intact benign endocervical glands (Figure 1d). On high-power examination, the individual tumor cells had intracytoplasmic vacuoles or lumina with characteristic magenta bodies. Immunohistochemistry (IHC) was done, which showed tumor cells were negative for p63, p16, and Her-2 neu. ER staining showed focal mild positivity (30% expression) and PR staining showed focal strong nuclear positivity (70% expression) (Figure 2). A diagnosis of lobular carcinoma metastatic to uterine cervix was made considering her history, the characteristic histo-morphology, and the IHC pattern. Fluoro-deoxy-glucose

positron emission tomography (FDG-PET) scan showed FDG-avid lesions (standardized uptake value [SUVmax] 14.9) in the cervix uteri, a satellite nodule in the corpus of the uterus and metastasis in the pelvic (SUVmax 11.7), and para-aortic lymph nodes (SUVmax 5.2) without any FDGavid lesions in the bilateral breasts or axillae (Figure 3).The differential diagnosis in this case included primary cervical adenocarcinoma or primary endometrial adenocarcinoma with lymph node metastasis. However, considering her history and the characteristic histological findings, she was deemed as most likely having metastatic lobular carcinoma, and was treated with combination chemotherapy. We posed the following clinical questions: (1) Is this a new primary cancer? How would this best be distinguished? And if so, are they related in a syndrome, versus explainable by other risk factors? (2) If metastatic from the patient’s

Late metastasis of lobular carcinoma of the breast

e83

Figure 2. A panel of microphotographs (a) ER showing focal mild nuclear positivity; (b) PR showing focal strong nuclear positivity; (c) p16-negative; (d) p63-negative (Immunostains 100x).

Figure 3. Clinical drawings and images from FDG-PET scan. (a & b) Time of diagnosis of cervical cancer. © Whole body maximum intensity projection of the PET scan showing uptake in the pelvis and along the nodes and no FDG uptake is seen in the breast. (d, e, & f) PET-CT registered images showing growth in the cervix and metastatic pelvic and para-aortic nodes without uptake in the breast or axilla.

e84

original breast cancer, how would one approach her treatment at this time, with endocrine, single-agent or combination chemotherapy? Multimodality therapy? And for what goals of treatment?

Pathologist’s Expert Opinion This case shows a poorly differentiated carcinoma showing a linear growth pattern and discohesive cells. The cells are more pleomorphic than typically seen in classic lobular carcinomas as could be seen in a higher grade ILC. While ER/PR expression is most commonly associated with breast carcinomas, gynecologic tumors, such as endometrial endometrioid carcinomas, are also known to express ER/PR; therefore, the expression of hormone markers cannot exclude a gynecologic malignancy. In this patient, the tumor was found in the cervix and therefore primary cervical carcinomas were considered. Immunostains showed the tumor to be ER/PR-positive and p16- and p63negative. p63 is one of the markers of squamous cell carcinomas and p16 is overexpressed in human papillomavirus (HPV)related carcinomas such as cervical squamous cell carcinoma and cervical adenocarcinoma. The lack of p63 and p16 expression in addition to the morphology effectively excluded both of these entities. Poorly differentiated endometrial adenocarcinoma also could have been considered. In this case, the expression of ER/ PR made a diagnosis of endometrial adenocarcinoma less likely as poorly differentiated endometrial adenocarcinomas tend to lose expression of ER/PR. Other markers that can help distinguish between breast and gynecologic malignancies include the recently identified immunostain GATA3 that is highly sensitive for breast carcinoma.16 In this case, the morphology and immunophenotype

A.G. Waks et al

strongly supported a diagnosis of metastatic lobular carcinoma. The patient has a history of ILC 15 years ago. The absence of radiologic and clinical evidence for tumor in the breasts does not support a new breast primary/ local recurrence. Only if the patient underwent subsequent bilateral mastectomies and pathology demonstrated the presence of invasive lobular carcinoma could local recurrence be definitively established. ILC shows clinical and prognostic differences from IDC such as being more likely to be multifocal and bilateral. As mentioned, it also tends to metastasize more frequently to the gastrointestinal and gynecologic organs and peritoneum than does IDC.17 In addition, women with ILC tend to be older than those with IDC (64.6 v 60.6 years of age).7 One distinct aspect of this case is that the patient developed ILC at a young age. This contrasts with the known association of aggressive tumors, ie, triple-negative (ER/PR/ Her2-negative) tumors in younger women with decreased survival.18 Late recurrences are not that unusual in breast carcinoma, with latency periods of 20–25 years reported.19 In ER-positive tumors, half of recurrences will occur after 5 years, in contrast to ER-negative tumors where recurrences are rare after 5 years.20 Similarly, ILC shows an early advantage in disease-free survival versus a late advantage for IDC after 6 years.8 This phenomenon of cancer recurrence after a prolonged diseasefree interval is known as tumor dormancy. The main working theories of tumor dormancy are that tumor cells either persist by withdrawing from the cell cycle, ie, become quiescent, and/or proliferate at a slow rate with concomitant cell death.21 The exact mechanism of tumor dormancy remains to be elucidated. In summary, the findings in this case are consistent with

late distant recurrence of lobular breast carcinoma with the late recurrence best explained by the concept of tumor dormancy. Helena Hwang, MD Department of Pathology University of Texas Southwestern Medical Center Dallas, TX

MULTIDISCIPLINARY ONCOLOGY OPINIONS Approximately 530,000 new cases of cervical cancer are diagnosed worldwide annually, accounting for an estimated 275,000 deaths.22 Eighty-six percent of new cervical cancer cases occur in developing countries lacking or having only limited screening programs.23 Globally, the cumulative risks of developing cervical cancer and of cervical cancer mortality by age 75 years were 1.9% and 1.1%, respectively.23 Lack of screening and chronic infection with HPV are necessary to the development of cervical cancer, and the presence of HPV has been documented in approximately 99.7% of cervical cancers worldwide.22 Squamous cell and adenocarcinoma, comprise the two major histologic subtypes of cervical cancer and share risk factors, including early onset of sexual activity, multiple sexual partners, high-risk sexual partners, history of sexually transmitted infections, history of vulvar or vaginal squamous intraepithelial neoplasia or cancer, immunosuppression, and, most importantly, lack of screening.25,26 Cervical cancer is staged clinically using the FIGO system, making staging more accessible in low-resource settings where this malignancy is more common.27 The definitive diagnosis of cervical cancer is made from tissue biopsy. In this case, it may be helpful to stain the biopsy tissue for HPV, given that cervical cancer would

Late metastasis of lobular carcinoma of the breast

be expected to stain positive for high-risk strains of HPV. Although integrated imaging with FDG-PET/ computed tomography (CT) is not part of the FIGO staging system, it can be helpful in delineating the extent of disease, specifically lymph node metastases, which may in turn aid in designing radiation fields. If a definitive diagnosis of cervical cancer is made in this case for the patient’s stage IIB lesion, she would be advised to undergo treatment with chemoradiation therapy. Although lymph nodal metastases do not alter FIGO staging, this finding impacts treatment. Several randomized trials have shown an overall survival advantage with use of concurrent chemotherapy as a sensitizing agent, along with radiation. Single-agent cisplatin, or combination cisplatin plus 5-FU, can be used as radiation sensitizers. Single-agent cisplatin is associated with similar outcomes to the doublet; however, it carries less toxicity.28–30 The differential diagnosis for this patient also includes a primary endometrial cancer. This patient was treated for breast cancer at the age of 38, and presumably she was premenopausal at the time. She went on to receive 5 years of tamoxifen. In postmenopausal women, tamoxifen use has been associated with an increased risk of endometrial carcinoma, but this same increased risk has not been established in premenopausal women.31,32 A definitive diagnosis would require a tissue sample from an endometrial biopsy or from a dilation and curettage procedure. Endometrial cancer is staged surgically. Although lymph nodal involvement is one of the most important prognostic factors in endometrial cancer, the role of lymphadenectomy in all patients with endometrial cancer remains controversial. If the diagnosis of endometrial cancer were confirmed in a patient with FDG-avid pelvic and para-aortic lymph

nodes and tumor involving the cervix, surgical treatment may be appropriate, assuming the disease is resectable. A pelvic magnetic resonance image (MRI) may help the clinical team to better delineate the anatomy of the cervical involvement. This patient had a PET scan that ruled out lung metastases. If the primary endometrial cancer is resectable, a radical hysterectomy with concomitant pelvic and para-aortic lymph node dissection would be appropriate for resection and tumor staging. It may be reasonable to perform the surgery laparoscopically given the results of a phase III randomized study of women with endometrial cancer performed by the Gynecologic Oncology Group. In this study, approximately 2,600 patients with uterine malignancy were randomized to either surgery by laparoscopy or laparotomy. Surgery included total hysterectomy and surgical staging, with both pelvic and paraaortic node dissection. Laparoscopic surgery was safe and feasible, with similar complication irrespective of surgical approach. Length of hospitalization was shorter for the women undergoing laparoscopic surgery, while cancer cure rates were similar between groups.33 In summary, from a gynecologic perspective the patient would be at risk of either cervical or endometrial cancer. Her age and potentially lack of cervical cancer screening are risk factors for cervical cancer, while her exposure to tamoxifen in the premenopausal state represents an undefined risk for the development of endometrial cancer. Histologic evaluation of the cervical biopsy is key in establishing the correct diagnosis as to whether this represents a new primary from the gynecologic tract versus recurrent/metastatic breast cancer. As presented, IHC studies were performed, which demonstrated that approximately 30% of tumor

e85

cells display weak nuclear staining for ER and approximately 70% of tumor cells display moderate to strong nuclear staining for PR. The tumor cells are nonreactive for p63, p16, and Her-2 neu (Figure 2). As discussed, the differential diagnosis in this case included primary cervical adenocarcinoma or primary endometrial adenocarcinoma with lymph node metastasis. However, the lack of staining for p63 and p16 makes cervical carcinoma less likely. GCDFP15 or mammoglobin markers would add information toward a breast origin. In conjunction with the patient’s clinical history of breast carcinoma, the architectural, cytologic, and IHC findings point to a diagnosis of lobular breast carcinoma. Lobular carcinoma has a propensity to metastasize to the peritoneum and gynecologic organs, as well as other organs, more so than ductal carcinoma of the breast. In addition, the pleomorphic type of lobular carcinoma has the tendency to behave more aggressively than the classical type. Considering her history and the characteristic histologic findings, she was deemed as most likely having metastatic lobular carcinoma.

Marcela G. del Carmen, MD, MPH Division of Gynecologic Oncology Vincent Obstetrics and Gynecology Massachusetts General Hospital Harvard Medical School Boston, MA Nicole B. Johnson, MD Beth Israel Deaconess Medical Center Boston, MA This case involves a 53-year-old woman with a past medical history of T2N1 ILC of the right breast 15 years prior, who now presents with a malignancy presumably involving the cervix, a satellite nodule in the corpus of the uterus,

e86

and pelvic and para-aortic lymph nodes. She was treated appropriately for the stage IIB, ER-positive breast cancer with surgery, chemotherapy, postoperative radiation, and 5 years of tamoxifen. Of note, the staging described in the case is pathologic staging, taking into account findings at the time of surgery such as tumor size (T), number of positive lymph nodes (N), and evidence of metastatic disease (M). The patient’s tumor was T2, indicating a primary from 2–5 cm in size, and N1, indicating that the breast cancer involved from one to three lymph nodes (at least 2 mm in size) in the right axilla. Using the risk-assessment tool Adjuvant Online, which predicts both risk of recurrence and benefits of therapy, this patient’s risk of recurrence over 10 years was 61% with local therapy alone.34 However, the aggressive treatment with chemotherapy followed by hormonal therapy brought her risk of recurrence down to 31% at 10 years.35 Unfortunately, in ER-positive breast cancer the risk of relapse remains an issue for many years, with a substantial number of the recurrences occurring after the 5 years of anti-estrogen therapy.35 The most common subtype of breast cancer is IDC, while lobular carcinoma, as in this case, only accounts for roughly 10%–15% of breast cancers, and tends to occur in postmenopausal women, be larger in size at time of diagnosis, and express ER and PR.7 Tumor registry data indicate that the metastatic spread between the two histologies, lobular and ductal, differs significantly in rates of metastasis to the gynecologic organs (4.5% v 0.8%), peritoneumretroperitoneum (3.1% v 0.6%), gastrointestinal system (4.5% v 0.2%), bone marrow (21.2% v 14.4%), lung pleura (2.5% v 10.2%) , and adrenal glands (0.6% v 0%).7,36 However, it is important to note that metastatic disease

A.G. Waks et al

within the cervix from a nongynecological primary is extremely rare, and most commonly arises from primary tumors of the gastrointestinal tract.37–44 When metastasizing to gynecological organs, breast cancer tends to spread to the ovary, with only 4.5% of cervical metastases originating from breast cancer.44,45 This phenomenon is likely due to the relatively small blood supply to the cervix, afferent lymph drainage, and a fibromuscular make-up that serves as a poor microenvironment for tumor cells.44 The rarity of metastasis from a non-gynecological primary to the female genital tract poses a diagnostic dilemma for pathologists and oncologists. The correct histological diagnosis is essential, because it has substantial implications for both treatment and prognosis; therefore an expert review of the pathology or a repeat biopsy is necessary in this case to distinguish a gynecological primary vs metastasis from the original breast cancer. Now that we have confirmed this represents a metastastic focus of lobular carcinoma, we can stage that patient as having stage IV or metastatic disease. This is currently considered to be incurable, and therefore the overall treatment goal becomes slowing the progression of disease, improving the quality of life, and prolonging her survival without causing significant side effects and toxicity with our treatments. The most frequent metastatic sites for breast cancer include bone, liver, and lung, with bone metastases being the most common for the hormone receptor-positive subtype; therefore, a bone scan would be beneficial. Since lobular carcinomas tend to be ER-positive and respond well to anti-estrogen therapy, if the patient is confirmed to be postmenopausal at the age of 53, the agent of choice would be an aromatase inhibitor (AI). Other

options for endocrine therapy include the anti-estrogen fulvestrant, and consideration of combination therapy with everolimus and the AI exemestane.46 Chemotherapy is an option in the future; however, it is not indicated as firstline therapy when anti-estrogen therapy options exist. Generally, the recommendation is sequential use of single-agent chemotherapy, except in the setting of visceral crisis or rapidly progressive disease, which requires prompt cytoreduction. It is important to note that combination chemotherapy has a higher response rate, but no benefit on overall survival versus a single agent in metastatic disease. Alternatively a clinical trial of a CDK 4/6 inhibitor in addition to an AI could be considered. This combination was recently studied in a phase II clinical trial, which showed a significantly improved progression-free survival (20.2 months with combination v 10.2 months with letrozole alone) in ER-positive breast cancer.47 Finally, it is imperative to emphasize that once breast cancer has metastasized the focus is largely on palliation. In the case of this patient, one should consider a radiation consult if the vaginal bleeding is significant enough to warrant immediate local therapy. Kerry Reynolds, MD Medical Oncologist Massachusetts General Hospital Boston, MA This is an unusual and fascinating case, one that exemplifies the need for an expert multidisciplinary team approach. The first step in our analysis was to confirm the pathologic diagnosis. We then discussed the clinical presentation and considered the possibility that there could be a second hidden malignancy in the body of the uterus, and also wondered if the patient’s burden of symptoms

Late metastasis of lobular carcinoma of the breast

required an urgent surgical approach or consideration of palliative radiation. Without such data (severity of bleeding, presence of symptomatic anemia or pain), we assumed there was no clinical urgency and invoked a single diagnosis, ie, metastatic lobular breast cancer. Endocrine-sensitive breast cancer, especially lobular breast cancer, can present with distant metastases many years or even decades after the original diagnosis. This is a very important concept to discuss with patients who are newly diagnosed and a reason to re-enforce the role of protracted adjuvant endocrine therapies. This patient was treated with 5 years of tamoxifen, as was the standard when she was initially diagnosed. If we consider what we have learned about endocrine therapy in the past 15 years, we would agree that this no longer constitutes the standard of care. Today, a 38-year-old woman considered to be at sufficient risk to warrant the recommendation of adjuvant chemotherapy, also needs to discuss other options for adjuvant endocrine therapy with her treating oncologist. She needs to think about the possible benefits of a longer course of tamoxifen (10 years instead of 5 years), and also about the possible benefit of adding ovarian suppression for up to 5 years, plus either tamoxifen or aromatase inhibition.48,49 These choices will entail tradeoffs between maintaining a better quality of life and avoiding menopausal symptom, versus risking more discomfort for several years for a possible future benefit. We speculated that this patient most likely had an early menopause as a result of her prior exposure to chemotherapy. It is worth noting that women who were initially premenopausal but then became menopausal after 5 years of tamoxifen, benefited from the sequential addition of an AI in the MA.17 clinical trial.50 This serves to highlight our

evolving knowledge of the usefulness of endocrine therapies, both upfront and delayed, for premenopausal breast cancer. This patient’s histology is that of a pleomorphic lobular cancer, a more aggressive biological subset among these tumors. The receptor staining for ER was not very intense (30%) but the PR staining was robust (70%). Hormonal therapy, with palliative intent, is the most appropriate treatment. After confirming her menopausal status, we would begin with an AI. There is no single treatment algorithm, but it is worth considering several lines of endocrine therapies before resorting to the more toxic treatments such as chemotherapy. There is considerable enthusiasm for the BOLERO 2 combination of everolimus and exemestane as a second-line therapy.46 Other options include the use of the anti-estrogen fulvestrant, as second- or third-line after progression on AIs. Unfortunately, despite early enthusiasm, the combination of fulvestrant with AIs is no better than either drug alone.51 If the patient has access to clinical trials, it is worth noting that novel therapies targeting the ER signaling pathways are showing excellent responses, even when the patient’s course suggests the tumor has acquired resistance to conventional treatments. Lidia Schapira, MD Division of HematologyOncology Massachusetts General Hospital Department of Medicine Harvard Medical School Boston, MA

MEDICAL ONCOLOGIST SPECIALIST EXPERT OPINION This particular case is unusual due to the site of presentation of the recurrent disease. After the biopsy of the cervix was found to be adenocarcinoma, the differential diagnosis included, but was

e87

not limited to, primary cervical adenocarcinoma or metastatic disease from the endometrium, ovary, stomach or breast. In this particular case the histology of the biopsied tissue raised the possibility of a diagnosis of metastatic lobular carcinoma of the breast. The histopathology of this tumor is characteristic for ILC and is not comparable to any type of primary cervical adenocarcinoma. The description of “small-sized tumor cells in single file pattern” is the hallmark characteristic of ILC. Also, the tissue was negative for p16, which is a marker for HPV infection. It is well known that HPV infection plays a major role in the development of cervical cancer. When HPV incorporates its viral DNA into the DNA of squamous epithelium, the oncoprotiens produced interfere with cell cycle–governing proteins such as p53 and retinoblastoma protein causing unregulated growth of the squamous epithelium of the cervix and thus leading to cervical cancer.52 The p16 stain detects this oncoprotein and is used as a marker for HPV infection. HPVnegative cervical cancers are extremely rare whether squamous or adenocarcinoma of the cervix.24 The tissue from the cervical biopsy in the patient described was negative for p16, making primary cervical cancer unlikely. Metastatic disease from a distant site such as stomach also would be unlikely as the PET scan did not reveal any other sites of disease. After reviewing all of the information and taking her medical history into account, the correct diagnosis of metastatic ILC from the breast was made. Now that the patient is diagnosed with symptomatic metastatic disease, the primary goals at this point would be to control of metastatic disease, palliation of symptoms, and minimizing treatment related toxicities to lessen the impact on her quality of life.53 The majority of patients with

e88

metastatic disease do ultimately die from their cancer, but this patient may have a more favorable long term prognosis. The potential for a better outcome is related to a number of factors: her tumor is hormone receptor-positive; there has been a long disease-free interval since her initial diagnosis and treatment; and, there is no evidence of visceral involvement, particularly lung or liver. She is symptomatic from the cervical disease with vaginal bleeding, which likely impacts her quality of life. Given her age and postmenopausal status, she is a good candidate for hormonal therapy with an AI.54 This has been shown to be an effective first-line therapy in metastatic breast cancer.55 Studies have been consistent with this being a more effective therapy when compared to tamoxifen and there would be less toxicity when compared to chemotherapy. If chemotherapy were to be used the preference would be single-agent chemotherapy to minimize toxicity. While combination chemotherapy is associated with a higher response rate, this is not a necessary consideration in view of the lack of rapidly progressive disease or visceral involvement. In addition, combination therapy would be associated with increased toxicity. If the vaginal bleeding was considered to be a more immediate problem or became more problematic then one could consider radiation therapy to the cervix, utilizing external-beam radiation with palliative intent. As this patient was diagnosed with breast cancer prior to the age of 50, she would meet the criteria for genetic testing for hereditary breast and ovarian cancer syndromes such as BRCA1 and BRCA2.56 Also, we would evaluate this patient for the germline mutations in CDH1 and PALB2.57 It has been shown that there is an association with CDH1 mutations and ILC even in the absence of other known malignancies.58 The

A.G. Waks et al

results of the genetic testing would not impact her current treatment plan but might prompt prophylactic bilateral oophorectomy for this patient as well as risk-reducing counseling for her family members. James Lennon, DO The Lankenau Medical Center Paul B. Gilman, MD The Lankenau Medical Center Main Line Health System Sydney Kimmel Medical College of Thomas Jefferson University Philadelphia, PA

MEDICAL ONCOLOGISTS’ EXPERT OPINIONS The phenomenon of delayed cancer recurrence is well described in ER-positive breast carcinoma. Approximately 2 years following diagnosis, the risk of ER-positive breast cancer recurrence stabilizes at 1.5%–2% per year, where it remains for over a decade. By contrast, patients with ER-negative disease have an annual recurrence risk of 7.5% in the second year following diagnosis, after which the risk steadily declines. Long-term ERpositive breast cancer survivors therefore are at ongoing risk of disease recurrence, often 10–20 years after their original diagnosis,59 as reflected by this patient’s history. Conversely, recurrence of hormone receptor-negative/ HER2-negative disease (also known as triple-negative disease) after 7 years is extremely unlikely.60 Therefore, the clinical history of uterine metastasis diagnosed 15 years after primary therapy is quite characteristic of an ERpositive lobular breast carcinoma. These features, in addition to the pathologic description of the cervical tumor, make it highly unlikely for the patient to have a new primary cervical cancer. Our current knowledge of inherited

cancer syndromes does not link the diagnoses of primary breast and primary cervical cancers, though the co-occurrence of breast and cervical cancers in a patient with Peutz-Jeghers syndrome has been described.61 Infection with HPV, the has no known association with breast cancer.62 However, given our patient’s young age at diagnosis, she does warrant genetic testing for germline BRCA1 and BRCA2 mutations, if not more comprehensive panel testing.52 A mutation identified in either BRCA gene could have implications for future therapeutic options, since BRCA-associated breast cancer is particularly sensitive to poly ADPribose polymerase (PARP) inhibitors, a novel therapeutic class,63 and to platinum-type chemotherapy.64 Treatment decisions made for this patient’s postmenopausal metastatic breast cancer must take into account the symptoms associated with her disease, which appear to be minimal postcoital bleeding. As she has stage IV disease, the goal of therapy is to prolong life and improve quality of life, but unfortunately current therapies cannot achieve cure. Systemic therapy is the single modality used in most cases; local modalities such as surgery and radiation therapy may rarely be used to palliate symptoms such as uncontrolled uterine bleeding but are not indicated in this case. In general, sequential single-agent endocrine therapy, as opposed to chemotherapy, should be used in first-line treatment of hormone receptor-positive metastatic breast cancer. Data support similar survival outcomes between the two approaches, while toxicity is greater with chemotherapy administration.65 Patients with advancedstage hormone receptor-positive disease who are not appropriate for a first-line endocrine therapy approach are those presenting with visceral crisis, rapidly progressive

Late metastasis of lobular carcinoma of the breast

metastatic disease, or endocrineresistant disease as evidenced by disease progression while on or shortly (1–2 years) after completing therapy with an endocrine agent in the adjuvant setting.66 Our patient completed her adjuvant tamoxifen therapy approximately 10 years prior; therefore, assuming her postcoital bleeding is not severe or rapidly progressive, she does not fit into any of the categories that dictate the use of first-line chemotherapy. AIs, which are effective only in postmenopausal women and function by blocking conversion of peripheral androgens to estrogens, are the first-line endocrine therapy of choice for postmenopausal metastatic breast cancer.67 Multiple randomized trials and metaanalyses have shown thirdgeneration AIs (letrozole, anastrozole, and exemestane) to be superior to tamoxifen in terms of overall survival in this patient population, offering an 11% reduction in risk of death compared to tamoxifen.67 Combination therapy with an AI plus fulvestrant, an estradiol analogue that accelerates degradation of the estrogen receptor, has been examined with mixed results. A randomized phase III Southwestern Oncology Group (SWOG) study found that both progression-free survival and overall survival were superior with combination anastrozole plus fulvestrant than with anastrozole alone for first-line treatment of postmenopausal advanced breast cancer.68 However, the generalizability of these results has been criticized based on the fact that less than half the patients enrolled in this study had received prior adjuvant tamoxifen, which is not representative of standard practice patterns in the United States. In the similarly structured FACT (Fulvestrant and Anastrozole Combination Therapy) study, a randomized phase III trial of first-line anastrozole plus fulvestrant versus anastrozole alone, there were no

significant differences in time to disease progression (10.8 months v 10.2 months for combination therapy and single-agent anastrozole, respectively) or overall survival (37.8 months v 38.2 months, respectively). Two thirds of FACT trial patients had received previous adjuvant endocrine treatment, as had our patient.69 Based on these results, single-agent AI therapy remains the standard of care for first-line treatment of postmenopausal women with hormone receptor-positive disease. In February 2015 the US Food and Drug Administration (FDA) granted accelerated approval to the cyclin-dependent kinase (CDK) 4/6 inhibitor palbociclib combined with the nonsteroidal AI letrozole for the first-line treatment of hormone receptorpositive breast cancer. Approval was based upon results from the PALOMA-1 study, an open-label randomized phase II trial in which palbociclib plus letrozole demonstrated a significant progressionfree survival advantage over letrozole alone (20.2 months v 10.2 months, respectively).47 It remains to be seen how quickly palbociclib will be incorporated into clinical practice; overall survival data from PALOMA-1, as well as data from a similarly designed phase III trial, are not yet mature. Evolving data suggest that single-agent fulvestrant may have a role in the first-line therapy of metastatic disease. The FIRST (Fulvestrant First-Line Study Comparing Endocrine Treatments) trial, a randomized phase II study of fulvestrant alone versus anastrozole alone for first-line treatment of advanced hormone receptorpositive postmenopausal breast cancer, found significantly higher median overall survival in patients treated with fulvestrant versus anastrozole (54.1 months v 48.4 months, respectively).70 However, this finding has not yet been validated in a phase III study; the ongoing FALCON (Fulvestrant

e89

and Anastrozole Compared in Hormonal Therapy Naı¨ve Advanced Breast Cancer) trial is evaluating this question.71 Multiple strategies exist for second-line therapy and beyond following disease progression on first-line single-agent AI. Addition of targeted agents to endocrine therapy has been shown to overcome endocrine resistance and improve survival outcomes. The mammalian target of rapamycin (mTOR) inhibitor everolimus in combination with exemestane (a steroidal AI) is FDA-approved for the treatment of hormone receptor-positive disease that has progressed after treatment with a nonsteroidal AI (letrozole or anastrozole) based on the results of the BOLERO-2 (Breast Cancer Trials of Oral Everolimus-2) trial.72 In addition, the CDK 4/6 inhibitor palbociclib is currently being investigated in hormone receptorpositive metastatic disease with acquired resistance to endocrine therapy.73 Chemotherapy is ultimately indicated in the treatment of hormone receptor-positive metastatic disease when endocrine therapybased options are exhausted or found to be ineffective after several sequential regimens have been utilized. Sequential monochemotherapy is generally recommended over combination regimens in the metastatic setting. Both anthracyclines and taxanes have shown excellent singleagent activity in metastatic disease74 and either would be an excellent choice for this patient at the time of chemotherapy initiation, as she received neither in the adjuvant setting. In conclusion, for the patient in question we would recommend first-line systemic endocrine therapy with an AI for her newly diagnosed metastatic ILC. Though her malignancy unfortunately cannot be cured, there is a promising arsenal of endocrine, targeted, and chemotherapeutic agents both

e90

approved for standard use and in ongoing development, and thus plentiful reason to hope for multiple years of good quality life ahead. Adrienne G. Waks, MD Dana-Farber Cancer Institute, Boston, MA Beth Overmoyer, MD Susan F. Smith Center for Women’s Cancers, Dana-Farber Cancer Institute Harvard Medical School Boston, MA

DISCUSSION This case is presented as a quandary for the practicing oncologist in a woman with a distant history of ILC; the diagnostic difficulties for the origin of her current cervical tumor create a clinical dilemma. The occurrence of late metastasis of a lobular carcinoma in such an unlikely site after 15 years of putative “dormancy” is a matter for speculation and debate. The major differential diagnoses in this patient include metastatic lobular carcinoma, carcinoma of the cervix uteri (FIGO IIB), and endometrial cancer (FIGO IIIC2). Favoring lobular carcinoma were the characteristic histology, ER and PR positivity, and negativity for p63 and p16 protein, the latter of which is overexpressed in all cervical cancers caused by intermediate- and high-risk HPV serotypes.75 The former, p63, is helpful in distinguishing poorly differentiated squamous cell carcinoma from small cell carcinoma or adenocarcinoma,76 as it can be strongly expressed in poorly differentiated squamous cell cancer (with a specificity of 86%) but is negative in small cell or adenocarcinoma.77 Lobular carcinomas have been shown to have significantly less FDG avidity on PET scanning as compared to ductal carcinomas, and are considered a major cause of false negative FDGPET scans in breast cancer78; thus

A.G. Waks et al

confusing the clinical picture in this case were the high FDG avidity of the lesions mitigating against lobular carcinoma. From a treatment point of view, surgery was not a favorable option as metastatic cancer was likely, and even if considering cervical and endometrial cancer, both were locally advanced enough to further require adjuvant chemotherapy and radiotherapy. Radiation therapy, would entail a large pelvic/ para-aortic field, causing yet more morbidity than reasonable benefit. Chemotherapy, then, was the most feasible option that could address all possible clinical scenarios, and hence the patient was started on a taxaneand anthracycline-based regimen (with radiotherapy being reserved for any residual lesion left behind after chemotherapy). She is recommended to also receive an aromatase inhibitor after completion of the chemotherapy in the event of a good clinical response or remission. Literature exists of metastasis from primary breast cancer occurring to the female genital organs, with the most common site being the ovary.79 There have been 34 cases in the literature of breast cancer with metastasis to the cervix, of which seven were of the lobular variety. In most of these instances, the presentation was that of an advanced breast and cervical cancer with metastasis detected at time of presentation.80,81 Incidental findings of cervical metastases at the time of autopsy is more common, and often have not manifested in symptoms of cervical involvement. The mean interval in the literature between the breast primary and cervical metastasis is 34.3 months.80 Occasionally, involvement of the uterus or cervix have presented with abnormal vaginal bleeding, and can now be diagnosed via liquid-based cytology.82 In the present case, the interval was 180 months which can suggest the concept of “cancer

dormancy”, where microscopic metastases eventually progress to overt cancer after being undetectable for a long period of time; breast and prostate cancers are classical examples of this behavior. Such late metastatic occurrences have been linked to ER positivity; recapitulation of the natural progression of this phenotype includes tumorigenesis, local invasion, vascular invasion and metastasis, predominantly to bone.83 In this case, our patient had previously received tamoxifen for 5 years when she was premenopausal. She developed metastasis after attaining menopause, which suggests that the peripheral sources of estrogens may have played a role in recurrence and metastasis after such a long period. New data from the ATLAS and AtTOM trials48,84 may give credence to extending tamoixfen therapy to 10 years for higher risk women, or the addition of 5 years of AI may be justified after 5 years of tamoxifen therapy per National Comprehensive Cancer Network (NCCN) guidelines.66 In addition, as mentioned by Drs Lennon, Gilman, Waks, and Overmoyer, testing for genetic mutations is paramount to comprehensive care of the patient and her first-degree relatives. In conclusion, the important teaching point from this report is the consideration of late metastasis rather than a second primary when a woman with history of ILC presents with a second malignancy. In such a situation, the findings of the pathologist must be correlated with the compelling clinical and radiological. This case also re-invokes the continuing debate as to what should be the optimal duration of anti-estrogen therapy in patients with earlystage breast cancer particularly for the ER-, PR-expressing variety of lobular cancer. In addition, this discussion further highlights the importance of considering firstline endocrine therapy as effective strategy for metastases for lobular

Late metastasis of lobular carcinoma of the breast

carcinoma. To this end, novel AI combinations as well as CDK 4/6 inhibitors are specifically discussed by Drs Reynolds, Shapira, Waks, and Overmoyer. It is important that clinicians be cognizant that ILC has a much wider and different pattern of metastatic disease when compared to IDC. Metastatic ILC must be in the differential diagnosis in a patient with a history of ILC presenting with abdominal complaints or an incidental finding seen on screening imaging, even if the patient has been disease-free for several years. We greatly appreciate the expertise of this internationallyrecognized multidisciplinary and multiregional panel. Budhi S. Yadav, MD Radiation and Medical Oncology Post Graduate Institute of Medical Education and Research Chadigakhr, India Edited by Dr Gloria J. Morris

Acknowledgment Dr Yadav also wishes to acknowledge the following colleagues and contributors: Dr Vjaisimha, Senior Resident, Radiation Oncology; Dr Nalini Gupta, Associate Professor, Histopathology; Dr Ashwani Sood, Assistant Professor, Nuclear Medicine; Dr Labeeb Mohd Abrar, Senior Resident, Nuclear Medicine; Post Graduate Institute of Medical Education and Research, Chadigakhr, India.

REFERENCES 1. Martinez V, Azzopardi JG. Invasive lobular carcinoma of the breast: incidence and variants. Histopathology. 1979;3(6):467–88. 2. Sobinsky JD, Willson TD, Podbielski FJ, Connolly MM. Case report: unusual metastatic patterns of invasive lobular carcinoma of the breast. Case Rep Oncol Med. 2013; article ID 986517; http://dx.doi.org/10. 1155/2013/986517.

3. Winston CB, Hadar O, Teitcher JB, et al. Metastatic lobular carcinoma of the breast: patterns of spread in the chest, abdomen, and pelvis on CT. AJR Am J Roentgenol. 2000;175: 795–800. 4. Lamovec J, Bracko M. Metastatic pattern of infiltrating lobular carcinoma of the breast: an autopsy study. J Surg Oncol. 1991;48: 28–33. 5. Saranovic D, Kovac JD, Knezevic S, et al. Invasive lobular breast cancer presenting an unusual metastatic pattern in the form of peritoneal and rectal metastases: a case report. J Breast Cancer. 2011;14:247–50. 6. Harris M, Howell A, Chrissohou M, et al. A comparison of the metastatic pattern of infiltrating lobular carcinoma and infiltrating duct carcinoma of the breast. Br J Cancer. 1984;50:23–30. 7. Arpino G, Bardou VJ, Clark GM, Elledge RM. Infiltrating lobular carcinoma of the breast: tumor characteristics and clinical outcome. Breast Cancer Res. 2004;6 (3):R149–56. 8. Pestalozzi BC, Zahrieh D, Mallon E, et al. Distinct clinical and prognostic features of infiltrating lobular carcinoma of the breast: combined results of 15 International Breast Cancer Study Group clinical trials. J Clin Oncol. 2008; 26:3006–14. 9. Lal P, Tan LK, Chen B. Correlation of HER-2 status with estrogen and progesterone receptors and histologic features in 3,655 invasive breast carcinomas. Am J Clin Pathol. 2005;123:541–6. 10. Kumar V, Abbas A, Fausto N, Mitchell R. Robins basic pathology. Philadelphia: Elsevier; 2007. 11. Rakha EA, van Deurzen CH, Paish EC, et al. Pleomorphic lobular carcinoma of the breast: is it a prognostically significant pathological subtype independent of histological grade? Mod Pathol. 2013;26:496–501. 12. Krecke K, Gisvold J. Invasive lobular carcinoma of the breast: mammographic findings and extent of disease at diagnosis in 184 patients. AJR Am J Roentgenol. 1993;161:947–60. 13. Kumar NB, Hart WR. Metastases to the uterine corpus from extragenital

e91

14.

15.

16.

17.

18.

19.

20.

21.

22.

23.

24.

cancers. A clinicopathologic study of 63 cases. Cancer. 1982;50:2163–9. Lehr H, Folpe A, Yaziji H, Kommoss F, Gown AM. Cytokertatin 8 immunostaining pattern and Ecadherin expression distinguish lobular from ductal breast carcinoma. Am J Clin Pathol. 2000;114: 190–6. Da Silva L, Parry S, Reid L, et al. Aberrant expression of E-cadherin in lobular carcinomas of the breast. Am J Surg Pathol. 2008;32: 773–83. Liu H, Shi J, Wilderson ML, et al. Immunohistochemical evaluation of GATA3 expression in tumors and normal tissue: a useful immunomarker for breast and urothelial carcinoma. Am J Clin Pathol. 2012;138:57–64. Jain S, Fisher C, Smith P, et al. Patterns of metastatic breast cancer in relation to histological type. Eur J Cancer. 1993;29A(15): 2155–7. Fredholm H, Eaker S, Frisell J, et al. Breast cancer in young women: poor survival despite intensive treatment. Plos One. 2009;4:e7695. Karrison TG, Ferguson DJ, Meier P. Dormancy of mammary carcinoma after mastectomy. J Natl Cancer Inst. 1999;91:80–5. Blows FM, Driver KE, Schmidt MK, et al. Subtyping of breast cancer by immunohistochemistry to investigate a relationship between subtype and short and long term survival: a collaborative analysis of data for 10,159 cases from 12 studies. PLoS Mede. 2010;7: e1000279. Banys M, Hartkopf AD, Krawczyk N, et al. Dormancy in breast cancer. Breast Cancer. 2012;4:183–91. Cervical cancer incidence, mortality and prevalence worldwide in 2008: Summary. http://globocan. iarc.fr/factsheet.asp. Accessed December 29, 2014. WHO/ICO Information Center of HPV and Cervical Cancer (HPV Information Center). Human papillomavirus and related cancers in the world. Summary report 2010. http://www.who.int/hpvcentre/en/. Accessed December 29, 2014. Walboomers JM, Jacobs MV, Manos MM, et al. Human papillomavirus is a necessary cause of

e92

25.

26.

27.

28.

29.

30.

31.

32.

A.G. Waks et al

invasive cervical cancer worldwide. J Pathol. 1999;189(1):12–9. International Collaboration of Epidemiological Studies of Cervical Cancer. Comparison of risk factors for invasive squamous cell carcinoma and adenocarcinoma of the cervix: collaborative reanalysis of individual data on 8, 097 women with squamous cell carcinoma and 1,374 women with adenocarcinoma from 12 epidemiological studies. Int J Cancer. 2007;120:885. ˜ oz Castellsague´ X, Bosch FX, Mun N, et al. Male circumcision, penile human papillomavirus infection, and cervical cancer in female partners. N Engl J Med. 2002;346: 1105. Pecorelli S, Zigliani L, Odicino F. Revised FIGO staging for carcinoma of the cervix. Int J Gynaecol Obstet. 2009;105:107. Peters WA, 3rd, Liu PY, Barrett RJ, 2nd, et al. Concurrent chemotherapy and pelvic radiation therapy compared with pelvic radiation therapy alone as adjuvant therapy after radical surgery in high-risk early-stage cancer of the cervix. J Clin Oncol. 2000;18:1606. Chemoradiotherapy for Cervical Cancer Meta-analysis Collaboration (CCCMAC). Reducing uncertainties about the effects of chemoradiotherapy for cervical cancer: individual patient data meta-analysis. Cochrane Database Syst Rev. 2010; CD008285. Kim YS, Shin SS, Nam JH, et al. Prospective randomized comparison of monthly fluorouracil and cisplatin versus weekly cisplatin concurrent with pelvic radiotherapy and high-dose rate brachytherapy for locally advanced cervical cancer. Gynecol Oncol. 2008;108:195. Iqbal J, Ginsburg OM, Wijeratne TD, et al. Endometrial cancer and venous thromboembolism in women under age 50 who take tamoxifen for prevention of breast cancer: a systematic review. Cancer Treat Rev. 2012;38:318. Davies C, Godwin J, et al. Relevance of breast cancer hormone receptors and other factors to the efficacy of adjuvant tamoxifen: patient-level meta-analysis of randomised trials. Lancet. 2011;378: 771.

33. Walker JL, Piedmonte MR, Spirtos NM, et al. Laparoscopy compared with laparotomy for comprehensive surgical staging of uterine cancer: Gynecologic Oncology Group Study LAP2. J Clin Oncol. 2009;27:5331. 34. www.adjuvantonline.com. Accessed January 16, 2015. 35. Zhang Y, Schnabel CA, Schroeder BE, et al. Breast cancer index identifies early-stage estrogen receptor-positive breast cancer patients at risk for earlyand late-distant recurrence. Clin Cancer Res. 2013;19(15): 4196–205. 36. Borst MJ, Ingold JA. Metastatic patterns of invasive lobular versus invasive ductal carcinoma of the breast. Surgery. 1993;114 (4):637–41. 37. McCluggage WG, Hurrell DP, Kennedy K. Metastatic carcinomas in the cervix mimicking primary cervical adenocarcinoma and adenocarcinoma in situ: report of a series of cases. Am J Surg Pathol. 2010;34(5):735–41. 38. Yokoyama Y, Sato S, Futagami M, Saito Y. Solitary metastasis to the uterine cervix from the early gastric cancer: a case report. Eur J Gynaecol Oncol. 2000;21(5): 469–71. 39. Kashimura M, Kashimura Y, Matsuyama T, Tsukamoto N, Sugimori H, Taki I. Adenocarcinoma of the uterine cervix metastatic from primary stomach cancer. Cytologic findings in six cases. Acta Cytol. 1983;27(1):54–8. 40. Pe´rez-Montiel D, Serrano-Olvera A, Salazar LC, et al. Adenocarcinoma metastatic to the uterine cervix: a case series. J Obstet Gynaecol Res. 2012;38(3):541–9. 41. Nakagami K, Takahashi T, Sugitani K, Sasaki T, Ohwada S, Morishita Y. Uterine cervix metastasis from rectal carcinoma: a case report and a review of the literature. Jpn J Clin Oncol. 1999;29(12): 640–2. 42. Lemoine NR, Hall PA. Epithelial tumors metastatic to the uterine cervix. A study of 33 cases and review of the literature. Cancer. 1986;57(10):2002–5. 43. Mazur MT, Hsueh S, Gersell DJ. Metastases to the female genital

44.

45.

46.

47.

48.

49.

50.

51.

52.

tract. Analysis of 325 cases. Cancer. 1984;53(9):1978–84. Bryson CA, de Courcy-Wheeler RH, Wallace RJ. Breast cancer metastasising to the uterine cervix. Ulster Med J. 1999;68(1): 30–2. Chen P, Hu WM, Wang PH, Suen JH. Recurrent breast cancer presents as a single solid ovarian mass and ascites. Taiwan J Obstet Gynecol. 2006;45(4):356–9. Piccart M, Hortobagyi G, Campone M, et al. Everolims plus exemestane for hormone-receptor positive, human epidermal growth factor receptor-2 negative advanced breast cancer: overall survival results from BOLERO-2. Ann Oncol. 2014;25:2357–62. Finn RS, Crown JP, Lang I, et al. The cyclin-dependent kinase 4/6 inhibitor palbociclib in combination with letrozole versus letrozole alone as first-line treatment of oestrogen receptor-positive, HER2-negative, advanced breast cancer (PALOMA-1/TRIO-18): a randomised phase 2 study. Lancet Oncol. Dec 2014. Davies C, Pan H, Godwin J. Long term effects of continuing adjuvant tamoxifen to 10 years versus stopping at 5 years after diagnosis of oestrogen receptor positive breast cancer: ATLAS, a randomized trial. Lancet. 2013;381(9869): 805–16. Francis PA, Regan MM, Fleming GF. Adjuvant ovarian suppression in premenopausal breast cancer. N Engl J Med. 2014 Dec. Goss PE, Ingle JN, Martino S, et al. Impact of premenopausal status at breast cancer diagnosis in women entered on the placebo controlled NCIC CTG MA17 trial of extended adjuvant letrozole. Ann Oncol. 2013;24(2):355–61. Johnston SRD, Kilburn LS, Ellis P, et al. Fulvestrant plus anastrazole or placebo versus exemestane alone after progression on nonsteroidal aromatase inhibitors in postmenopausal patients with hormone-receptor positive locally advanced or metastatic breast cancer (SoFEA): a composite, multicenter, phase 3 randomised trial. Lancet. 2013;4:989–98. Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R. The E6

Late metastasis of lobular carcinoma of the breast

53.

54.

55.

56.

57.

58.

59.

60.

61.

62.

63.

and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol. 1989;63: 4417–21. Niederhuber J, Armitage J, Doroshow J, Kastan M, Tepper J. Abeloff’s clinical oncology. New York: Elsevier; 2014. Gibson L, Lawerence D, Dawson C, et al. Aromatase inhibitors for treatment of advanced breast cancer in postmenopausal women. Cochrane Database Syst Rev. 2009; CD003370. Nabholtz J, Buzdar A, Pollak M, et al. Anastrozole is superior to tamoxifen as first-line therapy for advanced breast cancer in postmenopausal women: results of a North American multicenter randomized trial. Arimidex Study Group. J Clin Oncol. 2000;18: 3758–67. National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology. Genetic/ familial high-risk assessment: breast and ovarian, Version 1.2014. Antonis C, Casadei S, Heikkinen T, et al. Breast-cancer risk in families with mutations in PALB2. N Engl J Med. 2014;371:497–506. Masciari S, Larsson N, Senz J, et al. Germline E-cadherin mutations in familial lobular breast cancer. J Med Genet. 2007;44:726–31. Anderson WF, Chen BE, Jatoi I, et al. Effects of estrogen receptor expression and histopathology on annual hazard rates of death from breast cancer. Breast Cancer Res Treat. 2006;100:121–6. Hess KR, Pusztai L, Buzdar AU, et al. Estrogen receptors and distinct patterns of breast cancer relapse. Breast Cancer Res Treat. 2003;78:105–18. Kilic-Okman T, Yardim T, Gucer F, et al. Breast cancer, ovarian gonadoblastoma and cervical cancer in a patient with Peutz-Jeghers Syndrome. Arch Gynecol Obstet. 2008;278:75–7. Oh JK, Weiderpass E. Infection and cancer: global distribution and burden of diseases. Ann Glob Health. 2014;80:384–92. Lee JM, Ledermann JA, Kohn EC. PARP inhibitors for BRCA1/2 mutation-associated and BRCA-

64.

65.

66.

67.

68.

69.

70.

71.

72.

like malignancies. Ann Oncol. 2014;25:32–40. Tutt A, Ellis P, Kilburn L, et al. TNT: a randomized phase III trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 breast cancer. San Antonio Breast Cancer Symposium. 2014;abstract S3-01. Wilcken N, Hornbuckle J, Ghersi D. Chemotherapy alone versus endocrine therapy alone for metastatic breast cancer. Cochrane Database Syst Rev. 2003 CD002747. NCCN Clinical Practice Guidelines in Oncology: Breast cancer. Version 3.2014:http://www.nccn. org, 2014. Mauri D, Pavlidis N, Polyzos NP, et al. Survival with aromatase inhibitors and inactivators versus standard hormonal therapy in advanced breast cancer: metaanalysis. J Natl Cancer Inst. 2006;98:1285–91. Mehta RS, Barlow WE, Albain KS, et al. Combination anastrozole and fulvestrant in metastatic breast cancer. N Engl J Med. 2012;367: 435–44. Bergh J, Jonsson PE, Lidbrink EK, et al. FACT: an open-label randomized phase III study of fulvestrant and anastrozole in combination compared with anastrozole alone as first-line therapy for patients with receptor-positive postmenopausal breast cancer. J Clin Oncol. 2012;30:1919–25. Robertson JFR, Llombart-Cussac A, Feltl D, et al. Fulvestrant 500 mg versus anastrozole as first-line treatment for advanced breast cancer: overall survival from the phase II “first” study. San Antonio Breast Cancer Symposium. 2014; abstract S6-04. A Global Study to compare the Effects of Fulvestrant and Arimidex in a Subset of Patients with Breast Cancer (FALCON). http:// www.clincaltrials.gov, Identifier: NCT01602380. Accessed January 30, 2015. Baselga J, Campone M, Piccart M, et al. Everolimus in postmenopausal hormone-receptor-positive advanced breast cancer. N Engl J Med. 2012;366:520–9.

e93

73. Palbociclib (PD-0332991) combined with Fulvestrant in Hormone-Receptor-Positive HER2Negative Metastatic Breast Cancer After Endocrine Failure (PALOMA3). http://www.clincaltrials.gov, Identifier: NCT01942135. Accessed January 30, 2015. 74. Cardoso F, Bedard PL, Winer EP, et al. International guidelines for management of metastatic breast cancer: combination vs sequential single-agent chemotherapy. J Natl Cancer Inst. 2009;101:1174–81. 75. Sano T, Oyama T, Kashiwabara K, Fukuda T, Nakajima T. Expression status of p16 protein is associated with human papillomavirus oncogenic potential in cervical and genital lesions. Am J Pathol. 1998; 153:1741–8. 76. Di Como CJ, Urist MJ, Babayan I, et al. p63 expression profiles in human normal and tumor tissues. Clin Cancer Res. 2002;8:494–501. 77. Kaufmann O, Fietze E, Mengs J, Dietel M. Value of p63 and cytokeratin 5/6 as immunohistochemical markers for the differential diagnosis of poorly differentiated and undifferentiated carcinomas. Am J Clin Pathol. 2001;116: 823–30. 78. Avril N, Menzel M, Dose J, et al. Glucose metabolism of breast cancer assessed by 18F-FDG PET: histologic and immunohistochemical tissue analysis. J Nucl Med. 2001;42:9–16. 79. Yadav BS, Sharma SC, Robin TP, et al. Synchronous primary carcinoma of breast and ovary versus ovarian metastases. Semin Oncol. 2015;42:e13–24. 80. Horikawa M, Mori Y, Nagai S, et al. Metastatic breast cancer to the uterine cervix mimicking a giant cervical leiomyoma. Nagoya J Med Sci. 2012;74:347–51. 81. Hepp HH, Hoos A, Leppien G, Wallwiener D. Breast cancer metastatic to the uterine cervix: analysis of a rare event. Cancer Invest. 1999;17:468–73. 82. Gupta N, Dudding N, Smith JH. Cytomorphological features of extra-genital metastases in SurePath cervical liquid-based cytology: a series of eight cases. Cytopathology. 2013;24:123–8. 83. Zhang XH, Giuliano M, Trivedi MV, Schiff R, Osborne CK.

e94

Metastasis dormancy in estrogen receptor-positive breast cancer. Clin Cancer Res. 2013;19:6389–97. 84. Gray RG, Rea D, Handley K, et al. aTTom: long-term effects of

A.G. Waks et al

continuing adjuvant tamoxifen to 10 years versus stopping at 5 years in 6,953 women with early breast cancer. 2013 ASCO Annual Meeting Plenary Session, Plenary

Session Including FDA Commissioner Address, Public Service Award, and Science of Oncology Award and Lecture. J Clin Oncol. 2013;31 (suppl): abstr 5.